Rheumatoid arthritis (RA) and its animal model collagen-induced arthritis (CIA) are known to be T and B cell dependent diseases. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to develop arthritis while DQ6 and DRB1*0402 provide protection. CIA susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies similar to that in patients. Absence of CIA and low cellular responses in B cell knockout mice suggests that the autoreactive B cells, in addition to producing antibodies may also be involved in presenting auto antigens to T cells. Improvement in ACR response criteria after depletion of B cells in patients further underscores the role of B cells in arthritis. However, the exact role of B cells in antigen presentation and their regulation in susceptible versus resistant strains of transgenic mice remains unclear. B cell function is regulated by B cell receptor, BCR, as well as other B cell specific receptors like BAFF-R. Our hypothesis is that B cells in transgenic mice carrying RA susceptible HLA gene have a defect in regulation which occurs through B cell receptor leading to hyperactivity and increased survival of autoreactive B cells. Females have hyperactive B cells which contribute towards the development of autoantibodies and presentation of antigens to T cells leading to increased incidence in females. Our preliminary data is consistent with this notion. Recent studies have shown that B cell responses are controlled by TLRs. In this study we will address the mechanism by which B cells contribute towards pathogenesis of collagen-induced arthritis in transgenic mice using mice expressing both CIA-susceptible and resistant HLA genes. In aim1, we will define the requirement of B cells as antigen presenting cells in pathogenesis of CIA. In aim 2 we will test our hypothesis if hyperactivity of B cell responses and epitope spreading in genetically susceptible mice leads to pathogenic response. Also, since not all transgenic mice positive for RA susceptible allele develop arthritis, potential differences in B cell activation status in those that develop arthritis versus that do not will be determined. In aim 3, we will determine the control of B cell responses by Toll like receptors, especially, TLR4 in this model. These transgenic mice and experiments proposed here should provide a mechanism of pathogenesis in context of B cells and narrow the focus of B cell-directed therapy. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is a disabling disease, affecting women more often than men. B cells produce rheumatoid factor and other autoantibodies. In this study we will use mice that express human arthritis associated genes to delineate the role of B cells in rheumatoid arthritis patients. These humanized mice mimic rheumatoid arthritis in pathology and sex-bias. Arthritic mice produce autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide antibodies that are used for diagnosis of rheumatoid arthritis. We will determine if B cells can present pathogenic antigen and if there is a defect in regulation of B cells in arthritis susceptible mice. The information gained using this unique model may be instructive in developing preventive immunointervention for ongoing arthritis especially in women.